Prevention strategies have been developed to take advantage of the metabolic and behavioral risk factors for type 2 diabetes that have been identified in research with the Pima Indians and elsewhere. Obesity, impaired glucose tolerance, hyperinsulinemia, physical inactivity, and high fat diet have been implicated as risk factors for type 2 diabetes. Since these factors are potentially reversible with behavioral and pharmacologic therapy, strategies for prevention have been developed and will be tested. This project is a multicenter randomized clinical trial of prevention of type 2 diabetes in overweight persons with impaired glucose tolerance known as the Diabetes Prevention Program. The first phase of the clinical trial was completed, resulting in a reduction of the incidence rate of diabetes by 31% by metformin and 58% by a lifestyle modification program. A genetics component has been added. Variants of the gene TCF7L2 were found to predict risk of diabetes in the clinical trial praticipants assigned to placebo. This excess risk was nearly eliminated in persons assigned to the lifestyle intervention program. A long-term follow-up is being conducted to study the sustainability of the preventive interventions.